A critical step in mRNA translation involves the recruitment of the 40S ribosome subunit to the 5' end of capped transcripts. Typically, an ensemble of multi-subunit translation initiation factors executes this task. Viruses provide attractive model systems to study this fundamental process, as they are obligate intracellular parasites, completely dependent upon the protein synthesis machinery resident in their hosts. As mRNA translation is necessary for their replication, viruses are proficient in manipulating not only the host cell translational machinery, but also effectively commandeer the cellular signaling pathways that regulate protein synthesis. This investigation concentrates on Herpes simplex virus-1 (HSV-1), a neurotrophic herpesvirus whose productive replication is responsible for a spectrum of human diseases ranging from self- limiting epithelial sores, severe ocular disease and life threatening encephalitis in immunocompetent hosts to disseminated disease in neonates and immunocompromised individuals. Our long - term objective is to understand how HSV-1 successfully engages and controls the cellular protein synthesis apparatus by both altering and remodeling translation initiation factor complexes required for the production of both cellular and viral polypeptides. As this process is of vital importance for reactivation from latency and vegetative viral growth, our analysis is likely to uncover new targets for potential therapeutic intervention. We specifically propose to i) understand the mechanism(s) whereby cellular translation factor complexes are altered as a result of HSV-1 infection; ii) investigate how the cellular translation repressor 4E- binding protein-1 is controlled in HSV-1 infected cells; and iii) determine how HSV-1 manipulates the cellular kinase mTOR to properly control viral protein synthesis. PUBLIC HEALTH REVELANCE: Like all viruses, herpes simplex virus-1 is completely dependent upon the machinery that produces proteins within its cellular host. By understanding how the virus captures and gains control of the cellular machinery, we hope to come up with new ways of interfering with virus growth. This is important because herpes simplex virus causes a spectrum of human diseases ranging from simple skin sores, to severe eye disease and life threatening brain infections in people with normal immune systems; in addition, the infections are particularly severe in newborns and individuals whose immune systems are not working properly.